tbuckley/cabot-search huggingface dataset:
Abstract 15484: Distinct Subcellular Localizations of Non-Muscle Myosin IIB and IIC in Cardiomyocytes
Authors: Brianna Andersen, Kazuhiro Omi, Jessica J Wang
Journal: Circulation (2022)

Introduction: Non-muscle myosin (NMII) contraction plays a role in generating cellular tension and its role in mediating myocardial hypertrophy is emerging. Non-muscle myosin is present in cardiomyocytes in two isoforms NMIIB and NMIIC. Prior literature suggests that NMIIB and NMIIC are found in the intercalated disc, while NMIIB is found in the Z discs. Recently, PKC was implicated in medating stiffness-dependent cardiomyocyte hypertrophy through NMII. Moreover, PKC and NMII were found to be upregulated at the costameres in heart disease. The respective role of NMIIB and NMIIC in mediating cardiac hypertrophy remains unknown. Methods: Cardiac tissues from 10w male C57BL6/J wildtype and Myh14-GFP mice were fixed in BE40 solution (70% ethanol, 1% glycerol, 0.5% glcial acetic acid, and 28.5% 0.5 x PBS) for 3 days. Tissues were washed in 70% ethanol and made into paraffin embedded sections. Sections were heated for 10 min at 50C, deparaffinized, washed in ethanol and rinsed in PBS. Antigen retrieval was performed by heating for 10 min in TET buffer (Tris-EDTA, pH9.0 and 0.05% Tween 20). After PBS rinse, sections were incubated in blocking buffer (3% NGS, 1% BSA, 0.15% Triton X 100, PBS) for 1 hour at RT. Then sections are incubated in primary antibodies in the blocking buffer for 1 hour at RT. After PBS rinse, sections were incubated in secondary antibodies in the blocking buffer for 1 hour at RT. After PBS rinse, sections were mounted in Vectashield with DAPI. Images were captured using a Nikon A1 confocal microscopy with 60X oil lens and 2X zoom. Results: NMIIB is expressed in a subset of intercalated discs and Z lines. NMIIC is expressed in a subset of intercalated discs and costameres. Phospho-Myosin light chain (P-MLC) partially co-localizes with NMIIC in the intercalated discs but is not found in costameres. Conclusions: NMIIB and NMIIC display distinct subcellular localization, including within the intercalated discs. Only NMIIB is found at Z lines. Only NMIIC is found at costameres. P-MCL is only found in the intercalated discs. These findings suggest differential regulation and function of NMIIB and NMIIC. Further characterization of specific subcellular NMIIB and NMIIC function may elucidate their respective roles in tensional homeostasis in the cardiomyocyte.
Abstract 15286: Prolonged Exposure to Pesticides and the Risk of Atrial Fibrillation: The Particular Case of Chlordecone
Authors: Feng Xiong, Patrice Naud, Colombe Roy, yanfen shi, Jean-Claude Tardif, Jean-Francois Tanguay, Martin G Sirois, Roddy Hiram, Alexia FUNDERE
Journal: Circulation (2022)

Introduction: Atrial fibrillation (AF) is the most common form of cardiac arrhythmia. Chlordecone (CLD) is a pesticide known for its carcinogenic effects. Data suggest that CLD may disrupt the activity of myocardial Na + /K + -ATPase, deregulate mitochondrial Mg2+/ATPase in cardiomyocytes (CM), and inhibit CM Ca 2+ /ATPase. Little is known about the link between CLD and AF. Hypothesises: 1. Prolonged exposure to CLD induces arrhythmogenic cardiac remodeling in rats. 2.Cycle of CLD-withdrawal is accompanied by reduction of CLD-induced AF vulnerability. Methods: Male Wistar rats (250g) were exposed to CLD (0.1 μg/L or 1 μg/L) diluted in their daily water for 28 days. Control rats (CTRL) received water without CLD. Starting on day 29, all animals were exposed to CLD-free water. Electrophysiological study (EPS), echocardiography, and cardiac optical mapping (OM) were performed at days 28 and 56 to study cardiac function and atrial conduction. Expression levels of genes and proteins involved in inflammation, fibrosis and senescence were quantified by histology, immunoblot and qPCR. Results: At D28, all CLD-rats developed AF while CTRL rats did not. Compared to CTRL, weight up-take and water consumption were lower in animals exposed to CLD, although their food consumption was higher. Echocardiography revealed that CLD animals showed increased left ventricular contractility and atrial filling compared to CTRL. Acute CLD contamination caused a decrease in atrial conduction velocity and atrial action potential durations determined by cardiac OM ex-vivo . A 28-days CLD-withdrawal cycle was accompanied by weight normalization, and attenuation of AF inducibility, without improving atrial fibrosis and AF duration. CLD also decreased right and left atrial p21 mRNA expression, an effect not reversed by CLD weaning. Conclusion: CLD exposure is associated with increased AF vulnerability. CLD-weaning decreased (without abolishing), cardiac fibrosis and AF susceptibility.
Abstract 15590: Smooth Muscle Specific Deletion of P90 Ribosomal S6 Kinase Alters the Vasomotor Response of Resistance Arteries
Authors: Ramon J Ayon, Yves T Wang, Jaspreet Kalra, Yen-Lin Chen, Maniselvan Kuppusamy, Zaneta Markowska, Zdravka Daneva, Swapnil K Sonkusare, Thu H Le, Avril V Somlyo
Journal: Circulation (2022)

Background: Smooth muscle (SM) contraction is triggered by Ca 2+ /calmodulin-dependent myosin light chain kinase (MLCK), which phosphorylates the regulatory light chain of myosin (RLC 20 ). However, additional regulatory mechanisms exist. We found that global Rsk2 KO mice had more dilated mesenteric arteries (MAs) with reduced myogenic tone and RLC 20 phosphorylation, and significantly lower blood pressure. Furthermore, RSK2-dependent activation of the Na + /H + exchanger resulted in an increase in pH i and increased Ca 2+ i transients. However, it is unclear whether our observations were due to developmental abnormalities observed in Rsk2 global KO mice. Hypothesis: RSK2 signaling in SM is a significant regulator of myogenic tone, arterial stiffness, and Ca 2+ signaling. Methods: To study the role of RSK2 signaling in vascular tone, we generated inducible SM-specific RSK2 KO mice. Detection of total and phospho proteins were determined by western blot. Pressure myography studies assessed vascular reactivity in 4 th - and 5 th -order MAs isolated from MYH11-Cre + Rsk2 fl/fl (RSK2 SM -/- ) and MYH11-Cre - Rsk2 fl/fl (RSK2 SM +/+ ) mice. We examined SM-specific Ca 2+ events in pressurized MAs by confocal fluorescent microscopy. Results: Western blot confirms knock down of RSK2 expression (~70%) in MAs and aorta. Intraluminal pressure-induced constriction of MAs is attenuated in RSK2 SM -/- . RSK2 SM -/- MAs display a delay in development of myogenic tone at 40 mmHg and decreased vascular stiffness, compared to RSK2 SM +/+ . Vasodilatory responses to Spermine NONOate (1-100 μM) in preconstricted (L-NNA; 10 μM) RSK2 SM -/- vessels were enhanced. RSK2 SM -/- MAs display fewer Ca 2+ events (97±19.6; n = 4) than RSK2 SM +/+ (400±24.5; n = 4) at 80 mmHg ( p = 0.0001). Additionally, Ca 2+ events are slower and longer-lasting in the RSK2 SM -/- . Decreased levels of p-RLC 20 are observed at 40 mmHg, but not 80 mmHg in RSK2 SM -/- vs. RSK2 SM +/+ mice, consistent with impeding tone development. Conclusion: RSK2 signaling contributes to myogenic tone and vessel stiffness by regulating sensitivity to NO, increasing Ca 2+ events, and RLC 20 activity. RSK2 signaling pathway is a potential therapeutic target for hypertension.
Abstract 15292: Il21R-AS1 Long Non-Coding RNA as Potential Regulator in Therapeutic Angiogenesis in Peripheral Arterial Disease
Authors: Anita Kovacs-Kasa, Murat M Koseoglu, Brian H Annex
Journal: Circulation (2022)

Background: Peripheral arterial disease (PAD) is the major complication of systemic atherosclerosis. The clinical complications are intermittent claudication (IC) or its more severe form, critical limb ischemia (CLI). Potential therapeutic agents, to treat PAD failed in clinical studies. Vascular endothelial growth factor (VEGF) induced significant edema with no clinical benefit. Still today, no medical therapy exists to improve perfusion in PAD. Our lab has been studying the role of the interleukin-21 receptor (IL21R) in therapeutic angiogenesis. IL21 is undergoing clinical studies but its ability to be a therapeutic may be limited. IL21R transcribes a single human long non-coding RNA, the IL21R- antisense 1 (IL21R-AS1), with no mice homolog. Its role in PAD is not established yet. Hypothesis: IL21R-AS1 can serve as an activator of IL21R signaling to mediate hypoxia-induced angiogenesis without increasing vascular permeability. Methods and Results: Plasma from patients with IC, CLI, and non-PAD controls was obtained from whole blood. IL21R-AS1 was elevated in the plasma of patients with CLI. IL21R-AS1 expression was higher in endothelial cells (ECs) under hypoxia (2% O 2 ) serum starvation (HSS), an in vitro model of PAD. To reduce the expression of IL21R-AS1 cells were transfected with gapmeR, and for the overexpression, IL21-AS1 pCMV-TnT plasmid was used. The knockdown of the IL21R-AS1 decreased tube formation in angiogenesis assay performed on growth factor reduced matrigel, while the overexpression of the lncRNA was pro-angiogenic in hypoxic endothelial cells. We detected IL21R-AS1 in the cytoplasm and showed its translocation to the cell surface in HSS. More importantly, in ECs under HSS, we detected IL21R-AS1 in IL21R immunoprecipitation samples; suggesting a direct interaction between IL21R-AS1 and the IL21R. Both IL21 treatment and IL21R-AS1 overexpression increased transendothelial resistance (TER) in hypoxic ECs, in contrast to the permeability induced by VEGF as measured by ECIS (Endothelial Cell Impedance Sensing). Conclusion: Collectively our data suggest that the lncRNA IL21R-AS1 serves as an activator of the IL21R that can mediate angiogenesis but without inducing vascular leakage.
Abstract 269: Comparison Of Coronary Anatomy And Percutaneous Coronary Intervention Between Patients Undergoing Conventional And Extracorporeal Membrane Oxygenation Resuscitation
Authors: Danilo Franco, Tomaz Goslar, Peter Radsel, Nicola De Luca, Emanuele Barbato, Marko Noc
Journal: Circulation (2022)

Introduction: Because reestablishment of spontaneous circulation (ROSC) is frequently not achieved by conventional cardiopulmonary resuscitation (C-CPR), selected patients undergo resuscitation with extracorporeal membrane oxygenation (E-CPR). If coronary cause is suspected, coronary angiography (CAG) and percutaneous coronary intervention (PCI) are performed. Hypothesis: Coronary anatomy in E-CPR patients is more complex. Despite decreased and retrograde aortic blood flow, PCI is feasible and successful. Methods: Forty-three consecutive E-CPR patients undergoing immediate CAG admitted between August 2013 to May 2022 were matched by sex and age with 43 patients with ROSC after C-CPR. Results: Except for increased body mass index (28.9 ± 4.6 vs 26.3 ± 2.7; p=0.002) and more smoking (79% vs 58%; p=0.021) in E-CPR group , there was no significant differences in patient characteristics. Arrest was witnessed in 100% in E-CPR and 93% in C-CPR (p=0.078), basic life support was performed in 100% and 84% (p=0.006) and initial shockable rhythm was present in 63% and 82% (p=0.054), respectively. Multivessel disease (60.4% vs 32.5%) and chronic total occlusion (27.9% vs 9.3%) were more prevalent in E-CPR group (Table). There was no difference in the incidence and distribution of the acute culprit lesion present in &gt;90%. Syntax score was significantly increased in E-CPR group. E-CPR patients received more stents (2.08 vs 1.38/patient) with increased total length (49.3 vs 27.7 mm). There was no significant difference in final TIMI 3 (88.9% vs 97.4%). Residual Syntax score remained increased in E-CPR group. Conclusion E-CPR patients have more extensive chronic coronary disease without significant difference in acute culprit lesion. More complex anatomy may be, in the setting of comparable initial resuscitation, responsible for C-CPR failure. PCI in E-CPR is successful but more complex with increased residual disease burden.
Abstract 15465: Associations Between Adherence to the Physical Activity Goal and Body Fat Changes in a MHealth Weight Loss Trial
Authors: Zhadyra Bizhanova, Susan M Sereika, Maria M Brooks, Bonny Rockettewagner, Jacob K Kariuki, Lora E Burke
Journal: Circulation (2022)

Introduction: To date, few studies have examined the effectiveness of using wearable devices for promoting physical activity (PA) and improving body composition. Hypothesis: Adherence to the study-defined PA goal would be associated with greater body fat loss at 12 months than 6 months among adults with overweight or obesity during a weight loss intervention. Methods: SMARTER was a 12-mo, 2 arm weight loss trial with random assignment to (1) self-monitoring (SM, n=251) of diet, PA and weight, (2) self-monitoring plus ≤3 tailored feedback messages/day (SM+FB, n=251). The primary outcome was percentage of body fat % change assessed using Tanita scales and a body fat analyzer at 6 and 12 months relative to baseline. Adherence to the study-defined PA goal was assessed using weekly Fitbit moderate- and vigorous-intensity PA equivalents relative to ≥300 min/week PA goal and multiplied by 100%. Linear mixed modeling was used to estimate the effect of the percentage of adherence to the PA goal on the percentage of body fat % change at 6 and 12 months. Results: Participants (N=502) were mainly female (79.5%), White (82.5%), mean (± SD) age of 45.0 ± 14.4 years and BMI of 33.7 ± 4.0 kg/m2. Changes in the percentage of body fat % were similar at 6 and 12 months (time: F=3.48, P=.06) or by treatment assignment (treatment x time: F=1.33, P=.25). Overall, percentages of adherence to the PA goal were associated with greater percentages of body fat % loss (b [95% CI] -0.06 [-0.09, 0.03], F=18.61, P&lt;.0001), which did not vary over time (PA adherence x time: F=2.88, P = .09). Finally, percentages of adherence to the PA goal moderated treatment effects (PA adherence x treatment: 0.05 [0.01,0.09], F = 4.69, P = .03), which did not vary over time (PA adherence x treatment x time: F = 0.29, P = .59). Conclusions: PA adherence was associated body fat loss, which did not vary at 6 and 12 months in adults with overweight or obesity. Future studies need to examine the effect of using wearable devices on body composition when targeting behavior changes.
Abstract 15755: Reduced STEMI Activations but Worse STEMI Outcomes During the COVID-19 Pandemic
Authors: Sayyad Kyazimzade, Azalfa Lateef, Cory Jackson, William Mostertz, Matthew Evans, Arasi Maran, Chris Nielsen, VALERIAN Fernandes
Journal: Circulation (2022)

Introduction: ST-elevation myocardial infarctions (STEMIs) are emergencies requiring rapid intervention. COVID-19 has been associated with a reduction in acute presentations to ER’s, however the effect on STEMI presentations (incidence, mortality, and severity) remains unclear. Methods: STEMI presentation data from 2012 to 2022 were obtained from our database. There were 647 STEMI activations pre-pandemic (81 per year) and 61 STEMI activations during the pandemic (30 per year). The STEMI activations were further characterized as false alerts or true STEMIs (undergoing emergent catheterization). Unpaired t-tests were conducted to analyze the difference between the groups. Results: The percentage of true STEMIs during COVID-19 was higher than pre-COVID-19 (85.9% vs 71.4%; p&lt;0.01 ). Mean age pre-COVID-19 vs during COVID-19 was 60.4 years vs 58.4 years, while male sex was equal between both groups (72% vs 75%). Mean peak troponin levels of patients presenting during COVID-19 were lower than pre-COVID-19 (16.9 ng/L vs 51.5 ng/L; p&lt; 0.03 ). The 30-day mortality rate was higher in the COVID-19 group than in the pre-COVID-19 (12.9% vs 9.8% p-value: NS) group. Use of mechanical support was higher during COVID-19, relative to pre-COVID-19 (21% vs 8.5%; p&lt;0.001 ). One young patient presented as a delayed STEMI with a post-infarct VSD ultimately needing cardiac transplantation during the pandemic. Conclusion: During COVID-19, the overall STEMI activations decreased significantly. There was a higher incidence of true STEMIs, demonstrated by a lower rate of false alerts. This suggests that patients with more severe symptoms came to the hospital while patients with less severe/atypical symptoms may have avoided care. Lower peak troponin levels, yet more severe clinical outcomes (increased need for mechanical circulatory support, and a trend towards worse mortality), suggests delayed STEMI presentations during the pandemic. Further investigation is needed, given the ongoing dynamic nature of the pandemic.
Abstract 15567: Pulmonary Artery Catheter Use is Associated With Lower Mortality in Cardiogenic Shock, Especially in Heart Failure Related Shock
Authors: Manreet Kanwar, Vanessa Blumer, Shashank S Sinha, Jaime Hernandez-Montfort, Arthur Reshad Garan, Yijing Zhang, BORUI LI, Paulina Baca, Fatou Dieng, Claudius Mahr, Neil Harwani, Daniel Burkhoff, Navin K Kapur
Journal: Circulation (2022)

Introduction: Recent analyses have shown an increase in the use of pulmonary artery catheter (PAC), with an associated survival benefit in patients with cardiogenic shock (CS). The impact of PAC use on clinical outcomes among patient with CS due to heart failure (HF-CS) versus acute myocardial infarction (AMI-CS) remains unclear. Methods: The Cardiogenic Shock Working Group (CSWG) registry contains real-world data from patients hospitalized with CS across 17 clinical sites between 2016-2020. For this analysis, outcomes in CS patients were analyzed based the presence or absence of PAC, severity of CS (Society for Cardiovascular Angiography and Interventions or SCAI staging) and underlying shock etiology (AMI-CS or HF-CS). Results: Of the 1,890 CS patients included in this analysis, 1473 (77.9%) received a PAC during hospitalization, 593 (31.4%) had AMI-CS (PAC: 485 [81.8%], No PAC: 108 [18.2%]) and 1055 (55.8%) had HF-CS (PAC: 834 [79.1%], No PAC: 221 [20.9%]). Use of PAC was associated with greater drug/device utilization, mechanical ventilation and hospital length of stay, regardless of CS etiology (all p&lt;0.001). Patients with a PAC had significantly less in-hospital mortality in the overall (31% vs 41%, p&lt;0.001) and HF-CS cohort (21% vs 38%, p&lt;0.001), with more significant differences seen in SCAI stages C (p&lt;0.001) and D shock (p=0.01). Presence of PAC was not associated with in-hospital mortality among AMI-CS patients (43% vs 41%, p=0.63), regardless of SCAI stage (all p&gt;0.1). PAC patients were more likely to undergo heart replacement therapy (HRT) when compared to those with no PAC (p&lt;0.05) (Table). Conclusions: Using a large contemporary real-world dataset of CS, we identified that PAC use is associated with less in-hospital mortality and greater HRT compared to patients not receiving a PAC, particularly among HF-CS patients. Further, prospective efforts to define which CS populations derive the greatest benefit from PAC-guided interventions are needed.
Abstract 15678: The Introduction of Novel Heart Failure Therapy in Patients With Non-Compaction Cardiomyopathy Leads to an Improvement of Heart Failure
Authors: Andraz Cerar, Sabina Frljak, Renata Okrajsek, Neza Zorz, Gregor Poglajen, Gregor Zemljic, Miran Sebestjen, Bojan Vrtovec
Journal: Circulation (2022)

Introduction: In patients with noncompaction cardiomyopathy (NCC) no heart failure (HF) therapy has been shown to improve the left ventricle ejection fraction (LVEF). Sudden cardiac death (SCD) or need for heart transplantation (HTx) or left ventricle assist device (LVAD) implantation have been described. The effect of novel HF therapy, such as angiotensin receptor and neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2i) remains unclear. Hypothesis: We sought to analyze a potential recovery of cardiac function in patients with NCC after introducing the novel HF therapy. Methods: We have prospectively enrolled 41 (33 male, 8 female) patients with NCC, confirmed by cardiac MRI from 2018 to 2021. The average age was 49±16.3 years. At inclusion, echocardiography was performed to determine the left ventricle end-diastolic diameter and volume (EDD and EDV) and LVEF; serum levels of NT-proBNP have also been obtained. ARNI and SGLT2i have been introduced into patients’ therapy and up titrated to maximal tolerated dose. After 1 year follow up investigations, performed at patients' inclusion, have been repeated. Results: Of 41 patients enrolled 23 patients (56%) had echocardiographic evidence of myocardial recovery (Group A), defined by improvement of LVEF above 40% (LVEF increased from 31±6.6% to 48±5.2%. 9 patients (22%) showed no significant LVEF improvement (Group B, LVEF increased from 26±8.0% to 33±2.6%). 9 patients were excluded (2 due to SCD, 7 had HTx or LVAD implantation performed). The two groups did not differ in sex (male 41% vs. 39% in Group B, P=0.51), age (51±17.2 years vs. 46±15.2 years, P=0.72), sodium (140±2.6mEq/L vs. 138±1.8mEq/mL, P=0.22), creatinine (82±24μmol/L vs. 87±18 μmol/L, P=0.51) or bilirubin levels (17±12μmol/L vs. 21±12μmol/L, P=0.42). When compared to Group B at inclusion, Group A had significantly higher LVEF (31,6±6,6% vs. 26,5±8,0% in Group B, P=0.033) and lower NTproBNP levels (1619±1505pg/mL vs. 4902±3795pg/mL, P&lt;0.001). Conclusions: In patients with NCC, the introduction of novel HF therapy seems to be connected with significant reverse remodelation of the myocardium. The improvement has been shown to be more pronounced in NCC patients with better LVEF and lower neurohormonal activation.
Abstract 15735: Acquired Long-QT Syndrome Due to Excessive Loperamide Use
Authors: Jumkhawala A Saahil, Kevin Chen, Majd Hemam, Perry Wengrofsky, Pallavi Solanki
Journal: Circulation (2022)

Background: Loperamide is an over-the-counter opioid used primarily to treat diarrhea. Toxicity is known to predispose patients to life-threatening QT-interval prolongation and ventricular dysrhythmias. Case: A 42 year-old man with a past medical history of palpitations, tobacco use disorder, chronic back pain, and opioid use disorder presented to the hospital for syncope. In the preceding days, he experienced three episodes of palpitations followed by dizziness that would cause him to lose consciousness and fall, lasting five seconds each. He noted a longstanding opioid use history for chronic back pain, initially treated with oxycodone at a maximum dose of 600mg daily with transition to heroin for a total of three months. The patient then self-managed his opioid dependence with loperamide five years prior to admission, initially using doses of 200 mg daily, followed by three years of taking 768mg of loperamide daily. In attempts to avoid known electrophysiologic complications, he co-administered vitamin C (12,000-14,000 mg daily), magnesium citrate (1200mg/day), D3 (4000u daily), fish oil, centrum multivitamin 2 pills daily, and zinc. In the Emergency Department, the patient was given was given intravenous calcium, amiodarone, and magnesium for recurrent pulseless ventricular tachycardia, ultimately defibrillated and converted to junctional bradycardia. He was admitted to the cardiac care unit. Left heart catheterization demonstrated nonobstructive coronary artery disease; transthoracic echocardiogram was only notable for ejection fraction of 45%. He was treated with transvenous pacemaker (TVP) placement with pacing at 100bpm. Because of increasing intensity of opioid withdrawal, TVP was removed and isoproterenol infusion was started, while initiating transition to suboxone for maintenance treatment. Conclusion: This is the highest reported dose of loperamide intoxication as a method to self-manage opioid dependence. Despite low addictive potential, loperamide may be used at higher doses for opioid dependence or its euphoric effects. Treatment of loperamide toxicity should be aimed at reducing the risk of cardiotoxicity and managing withdrawal symptoms during detoxification, given its variable half-life.